Addiction is a chronic, relapsing disorder characterized by compulsive drug intake and vulnerability to relapse after cessation. In rats with an escalated pattern of cocaine intake, we observed gene expression evidence of remodeling of intrinsic lateral hypothalamic (LH) circuitry, which could contribute to the transition to compulsie drug taking and addiction. In particular, development of compulsive cocaine intake under extended access conditions was characterized by increased expression of genes for pre- and post-synaptic proteins, suggestive of structural reorganization of LH intrinsic circuitry. Careful analysis of these gene expression data suggests the hypothesis behind the present Cutting-Edge Basic Research Awards (CEBRA) grant proposal that such changes are brought about by glutamate-driven metabolic plasticity. In fact, we observed that glial electrogenic Na+ dependent glutamate transporters were increased in the LH of rats with histories of escalated (compulsive) cocaine self-administration. Sodium-coupled re-uptake of glutamate by astrocytes results in the activation of the Na+/K+ ATPase triggering, in turn, glucose uptake by astrocytes and glycogenolysis leading to the production and release of lactate into the extracellular space. Consistently, we observed that cocaine self- administration results in increased extracellular lactate levels and that concomitantly with increased expression of the glial electrogenic Na+ dependent glutamate transporters, several genes involved in lactate transport between astrocytes and neurons also showed increased expression in the LH of rats with histories of escalated cocaine self-administration. To test the present hypothesis, in Specific Aim 1 we will investigate functional adaptations in the lateral hypothalamus by patch-whole cell recording before and after the transition to compulsive cocaine self-administration in orexin and MCH neurons. Even minor metabolic manipulations, such as overnight food deprivation, induce structural and functional synaptic changes in orexin neurons as does passive cocaine administration. In Specific Aim 2 we will investigate the effect of manipulating astrocytic glutamate re-uptake in the LH on the electrophysiology of orexin and MCH neurons by delivery of an adeno- associated viral vector (AAV) over-expressing the astrocyte glutamate transporter GLT1 under an astrocyte- selective promoter. This approach showed promise as an experimental gene therapy strategy for epilepsy.